Curr Hepatology Rep https://doi.org/10.1007/s11901-017-0380-8
DRUG-INDUCED LIVER INJURY (F BESSONE AND R ANDRADE, SECTION EDITORS)
Hepatotoxicity in Patients with Metabolic Syndrome: Causes and Consequences Jose Ignacio Vargas 1 & Juan Pablo Arab 1,2 & Fernando Bessone 3 & Maria Isabel Lucena 4 & Raul J. Andrade 4 & Marco Arrese 1,5
# Springer Science+Business Media, LLC 2017
Abstract Purpose of Review The purpose of this review was to analyze the current evidence regarding the incidence, mechanisms, and outcomes of drug-induced liver injury (DILI) and hepatotoxicity in patients with metabolic syndrome and nonalcoholic fatty liver disease. Recent Findings DILI is a complex clinical entity. Although uncommon, its incidence and diagnosis have been rising in recent years as basic research and clinical databases provide information about its etiology, clinical course, and prognosis. The prevalence of metabolic syndrome and non-alcoholic fatty liver disease is on the rise in western countries. Recently, features of the metabolic syndrome have been
identified as factors affecting the phenotype and evolution of DILI, both in pre-clinical and clinical research. Summary In the present review, we summarize current evidence regarding the influence of features of metabolic syndrome in the presentation, clinical course, and prognosis of DILI. Keywords Hepatotoxicity . Drug-induced liver injury . Metabolic syndrome . Dyslipidemia . Obesity . Arterial hypertension . Non-alcoholic fatty liver disease . Chronic liver diseases . Cirrhosis
Scope of the Problem This article is part of the Topical Collection on Drug-Induced Liver Injury * Marco Arrese
[email protected] 1
Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Diagonal Paraguay362, Santiago, Chile
2
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
3
Hospital Provincial del Centenario, Gastroenterology & Hepatology Department, University of Rosario School of Medicine, Rosario, Argentina
4
Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
5
Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
Drug-induced liver injury (DILI) is a complex condition, with undefined underlying mechanisms, with a wide range of clinical presentations, an important number of potentially causative agents, and absence of definitive markers, making its diagnosis and management a troublesome issue [1]. Certain variables such as compound-specific properties, genetic variations, and environmental factors may influence DILI occurrence and presentation [2•]. It has been also suggested that excess weight and several metabolic risk factors [including components of the metabolic syndrome (MetS), obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD)] may play a role in DILI presentation and outcome although evidence supporting this assertion is limited [3, 4]. Some basic science observations strongly support the notion that fat accumulation in the liver deters an increased vulnerability to tissue injury upon exposure of different noxious stimuli such as bacterial endotoxin or ischemia/reperfusion [5•]. However, few clinical data are available in this regard for drug-induced liver damage. In the present review, we aim
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to critically analyze the existing evidence regarding the potential mechanisms at play as well as the incidence and outcomes of DILI in patients with MetsS and NAFLD.
Obesity, MetS, and NAFLD: Intertwined Conditions Predisposing to Liver Injury Obesity and overweight states are a constantly growing epidemic affecting more than 1.9 billion adults worldwide [6]. Obesity-related diseases include disorders of virtually every body system with cardiovascular disorders and T2DM being the more common pathological conditions leading to increased mortality in obese or overweight subjects. Both cardiovascular diseases and T2DM occur preferentially in subjects having a cluster of metabolic abnormalities that define the MetS and include the following: increased fasting plasma glucose or T2DM, hypertriglyceridemia, low HDL cholesterol, increased waist circumference, and hypertension [7]. Accordingly, the most recent criteria to support as MetS being present is when three out of five factors coexist in a given individual. Most of the features of MetS are either cause or consequence of insulin resistance (IR), a central metabolic defect present in almost all subjects with obesity [7]. IR in turn critically determines the development of NAFLD, which is now recognized as the most common liver disease worldwide [8]. NAFLD refers to a spectrum of histological abnormalities in the liver spanning from isolated steatosis to nonalcoholic steatohepatitis (NASH), with the latter being characterized by steatosis, hepatocellular injury (defined by the presence of hepatocyte ballooning), and inflammatory changes with different degrees of fibrosis that may progress to cirrhosis [9]. The prevalence of NAFLD in obese patients correlates with body mass index and reaches figures of 70–90% in obese subjects, and most of patients with MetS have NAFLD [9]. Of note, the relation of NAFLD and MetS is bidirectional with the liver being more than only a passive target affecting the pathogenesis of the MetS and its complications [10]. Evidence from experimental studies suggests that excessive lipid accumulation in hepatocytes renders the liver more susceptible to injury. More than 20 years ago, Yang et al. showed that administration of endotoxin to Zucker rats with liver steatosis results in extensive liver necrosis [11]. Also, ischemia-reperfusion injury is increased in the steatotic liver [12]. The mechanisms underlying this injury-prone state are related to a myriad of alterations that play a role in NAFLD pathophysiology and are commonly present in the steatotic liver [13]. Among these alterations are depletion of antioxidant defenses (i.e., reduced cellular glutathione levels or decreased activity of antioxidant enzymes such as superoxide dismutase) [14], mitochondrial dysfunction [15], cellular ATP depletion [16, 17], and altered hepatocellular transport
and drug metabolism [18, 19]. Indeed, this set of dysfunctions may also have an impact on DILI predisposition by affecting the clearance of therapeutic drugs or enhancing ongoing lipotoxicity in hepatocytes [5•]. Animal studies assessing hepatotoxicity of several drugs (i.e., acetaminophen) have shown that NAFLD may increase the risk and the severity of liver injury. This seems not to be related to the extent of steatosis but rather due to an increased basal activity of hepatic cytochromes P450, more specifically of CYP2E1 [20]. Several studies have also shown changes in drug-metabolizing enzymes in experimental obesity/NAFLD, but some discrepancy exists due to the sex- or species-dependent differences as well as among the different experimental models (i.e., dietary vs. genetic) making difficult to estimate the importance of NAFLD-associated changes in human drug metabolism [19]. Of note, a large variability in the activity of drug-metabolizing enzymes has also been described in both obese and NAFLD patients [21•]. In summary, patients with obesity and MetS exhibit a high prevalence of NAFLD, which in turn render the liver more susceptible to injury through multiple mechanisms. NAFLD is also associated with changes in hepatic uptake, distribution, and metabolism and transport of different xenobiotics. These multiple alterations provide a mechanistic frame to explain an increased susceptibility of these patients to DILI.
DILI, Metabolic Syndrome, and NAFLD: Clinical Evidence on Incidence and Severity The clinical issue of DILI occurrence and severity in patients with MetS and NAFLD is complicated by the lack of solid data. With regard to incidence of DILI in NAFLD, two prospective, population-based studies do not mention metabolic variables (BMI, T2DM, or NAFLD) as predisposing factors for DILI [22, 23]. Also, large prospective registries of DILI usually do not mention NAFLD or its sharing metabolic risk factors as determining increased odds of hepatotoxicity [24–26]. When considering these studies, it should be kept in mind that some of them have been carried out in populations with low prevalence of obesity and T2DM (i.e., Iceland) and that data collection in multicenter registries usually do not include MetS or NAFLD as relevant variables present. Also, the number of events for individual drugs is usually small making it difficult to draw conclusions. Thus, the role of NAFLD as a risk factor for DILI might have been underestimated. One Italian study did show that patients with NAFLD are at higher risk of DILI compared to patients with HCV chronic hepatitis [44]. NAFLD had an OR of 3.95 for drug-related hepatotoxicity in obese middle-aged patients, but the number of events was also small. With regard to severity of DILI in patients with NAFLD or MetS, data from the most recent report of the DILIN initiative
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showed that the presence of pre-existing liver disease is a risk factor for a more severe form of DILI presentation and higher mortality [25]. The etiologies of pre-existing liver disease in this report were mainly chronic hepatitis C and NAFLD with the number of subjects with the latter etiology being small. Interestingly, in the group with pre-existing liver disease, the prevalence of T2DM was significantly higher than in those without previous liver disease. Since the presence of MetS was not assessed in this study, no conclusions can be drawn with regard to the relevance of MetS on DILI incidence or severity. Some components of MetS have been shown to be risk factors for chronicity (defined as no resolution of liver damage after 1 year of follow-up) following acute idiosyncratic DILI. A recent report of data from the Spanish DILI registry [27] indicates that dyslipidemia at baseline confers a relatively higher risk for chronic liver alterations [OR of 4.5 (p = 0.04)]. Incidence of chronicity after an acute episode of DILI was uncommon reaching 8% of patients enrolled in this registry. When evaluating drug groups, statins had the higher proportion of DILI cases evolving as chronic DILI. Also, in this report, metabolic risk factors such as hypertension, T2DM, and dyslipidemia were more frequent in the group that evolved as chronic DILI [27]. Finally, additional analysis from the Spanish DILI registry have also shown that overweight patients had more hypersensitivity features at presentation than normal-weight patients, particularly lymphopenia [28]. Also, patients with DILI with metabolic risk factors (dyslipidemia and hypertension) had a more frequent detection of autoantibodies, particularly antinuclear antibody. These differences in clinical presentation could also make more difficult the process of causality assessment in a suspected DILI episode. In summary, there is limited evidence supporting the notion that MetS, NAFLD, or other metabolic factors influence the incidence and severity of DILI. As MetS and NAFLD prevalence is rising and prospective registries include these variables in their data collection, it is likely that more clear data will become available regarding DILI in patients with these conditions.
assessment of causality are in use [29, 31], with the most recommended being the CIOMS-RUCAM scale [32••]. Since NAFLD, and particularly NASH, can produce chronic elevations in aminotransferases, its presence could be a confounding factor for DILI causality assessment. In fact, in the report of the DILIN study, patients with previous liver disease including NAFLD had a higher ambiguity in causality scores for DILI [25]. Of note, in NAFLD patients, elevated aminotransferases are usually of low magnitude [33], with predominance of ALT over AST, and it is uncommon that NAFLD presents with a cholestatic pattern of liver enzyme alterations [34]. Thus, the common criteria for acute DILI should usually capture cases in these patients. Recently, Dakhoul and Chalasani [35] proposed modifications to causality instruments including some specifically designed criteria for patients with underlying liver disease that considers taking into account some features of the existing liver disorder. Liver biopsy is sometimes performed in patients with DILI although histopathology seldom adds value to causality adjudication except in selected cases. However, when analyzing cases of DILI in patients with MetS, it should be kept in mind that the majority of patients will have NAFLD on liver biopsy. Thus, the diagnosis of NAFLD vs. DILI as the cause of liver disease should always be considered in the context of the specific patient. Of note, some drugs (i.e., amiodarone and tamoxifen, see below) can induce features of NAFLD on liver biopsy, such as microvesicular or macrovesicular steatosis with or without ballooning and steatohepatitis [36, 37].
Specific Drugs Related to Metabolic Syndrome, Liver Steatosis, and DILI Existing evidence suggests that causative drug agents of DILI appear to be similar in patients with MetS and in patients without this condition [25]. However, some specific agents deserve consideration due to the fact that they may be associated with a more severe DILI if metabolic risk factors are present, may directly cause fatty liver degeneration, or may aggravate pre-existing NAFLD.
Causality Assessment of DILI in the Context of MetS/NAFLD
Amiodarone
Causality assessment when an episode of idiosyncratic DILI is suspected is a troublesome issue [29]. DILI is a diagnosis of exclusion based on an accurate medical history and pharmacological interrogation, laboratory evaluations, and, sometimes, liver biopsy [1]. Together with a complete medical history and physical examination, minimal elements for the evaluation of a suspected DILI episode includes searching for evidence of underlying liver disease, viral and autoimmune serology, and imaging studies [30]. Several scales for
Amiodarone is a widely used drug in the treatment of arrhythmias [38]. Chronic use of amiodarone has been linked to varying degrees of hepatotoxicity, in most cases, producing a transient asymptomatic elevations of aminotransferases in a dose-related effect [39]. Liver failure is an uncommon event [40]. Cardiac disease, components of the metabolic syndrome, and NAFLD are closely related. A retrospective study of 409 patients receiving amiodarone for more than 60 days found that the presence of amiodarone hepatotoxicity and liver
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enzyme alterations was not related to the presence of MetS or right side cardiac dysfunction [41]. Statins Patients with MetS are frequently exposed to statins to treat hyperlipidemia. Since many patients with MetS have NAFLD, clinicians had significant concern on the safety of these drugs in this population because of the fear of hepatotoxicity. Indeed, statins have been shown to cause idiosyncratic DILI. In the report from the Swedish Adverse Drug Reactions Advisory Committee, statin-related DILI reached 1.2/100,000 users with the clinical picture being a cholestatic/mixed pattern in the majority of cases. In this report, there were three cases of acute liver failure resulting in either death or liver transplantation [42, 43]. In the report from the DILIN, 2.6% of 899 cases of DILI were attributed to statins with subtle differences between different agents (atorvastatin 1.0%, rosuvastatin 0.8%, pravastatin 0.4%, fluvastatin 0.2%, and lovastatin 0.2%) [25]. Thus, statinassociated hepatotoxicity seems to be uncommon [43]. Specific information regarding safety of statins in patients with MetS is limited. A recent prospective study by Bril et al. [44•] suggests that there should be no concern in prescribing statins in this population and that, given the increased cardiovascular risk of these subjects, statins should not be withheld in these patients. This is relevant as it has been reported that up to 50% of NAFLD patients with indication of statins do not receive hypolipidemic treatment [45]. Interestingly, recently published pre-clinical and clinical research has generated new perspectives on the use of statins in patients with chronic liver disease (CLD) suggesting that this family of drugs is actually safe to use in this patient population and may, moreover, have some beneficial effects as therapeutic agents in NAFLD/NASH and also on the natural history of cirrhosis and its complications due to its pleiotropic vascular and anti-inflammatory properties (reviewed in refs. [46] and [47]). In summary, the use of statins in patients with MetS and/or NAFLD seems to be safe and should be used when indicated. The protective effects of statins on liver injury in NAFLD/ NASH [46, 48] are promising but requires further confirmation. Methotrexate Methotrexate acts through the inhibition of nucleic acid synthesis [49]. It is commonly used to treat dermatological, rheumatological, and gastrointestinal diseases. Methotrexate has been linked to hepatotoxicity most commonly in patients with psoriasis than ones with rheumatoid arthritis, probably related to the higher prevalence of MetS and NAFLD in psoriasis patients [50]. Methotrexate-associated liver injury has been
described ranging from steatosis, to fibrosis and, uncommonly, cirrhosis [51]. Retrospective studies in psoriasis patients have shown a markedly increase in risk of fibrosis in patients with obesity or T2DM using therapy with methotrexate [52, 53]. Thus, patients who are treated with methotrexate should be screened for MetS and NAFLD, due to increased risk of methotrexate-induced liver injury. Tamoxifen Tamoxifen is a modulator of the estrogen receptor, used in the treatment of breast cancer as a partial agonist or antagonist according to target tissue [54]. Tamoxifen has been indicated as a promotor of NAFLD [55], and reports indicate that almost half of patients using tamoxifen develop fatty liver at 2 years of treatment [56] with a small proportion developing steatohepatitis [57] and, occasionally, cirrhosis [58]. Regression of steatosis is seen after 1.2 years when tamoxifen has been stopped [56]. It also has been described that tamoxifen promotes fatty acid synthesis [59], impairment of beta oxidation [60], and depletion of hepatic mitochondrial DNA [61], and decreases hepatic VLDL production and GH secretion, as mechanisms for liver steatosis [62]. Prevalence of NASH is higher in patients using tamoxifen when MetS and obesity are present [63]. Thus, it is likely that NAFLD may develop after tamoxifen treatment and that this agent eventually aggravates pre-existing NAFLD when metabolic factors are present. Interestingly, it has been shown that the development of NAFLD negatively impacts survival in early-stage breast cancer treated with tamoxifen [64]. Nucleoside Reverse Transcriptase Inhibitors (NRTI) It is being increasingly recognized that NAFLD is commonly diagnosed in HIV-infected individuals. Moreover, it has been suggested that in these patients, isolated steatosis may more often be due to NASH- and NAFLD-related fibrosis or cirrhosis [65]. On the other hand, NRTI have been associated with hepatic steatosis, particularly in women and obese individuals [66] and also with steatohepatitis due to multiple mechanisms including mitochondrial dysfunction, inhibition of human DNA polymerase, increased lipogenesis, and inhibition of hepatocellular lipid export (reviewed in [66]). Although possible, there is no data indicating that the presence of NAFLD or metabolic factors increases NRTI-associated hepatotoxicity. Chemotherapy Several chemotherapy regiments used for colorectal cancer have been associated to liver injury. Diverse types of injury have been described including sinusoidal obstruction syndrome (associated to oxaliplatin), hepatic steatosis [related to 5-fluoruracil (5-FU)], and chemotherapy-associated
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steatohepatitis [CASH] (most commonly linked to irinotecan) [67]. Interestingly, liver fat content may increase by more than 30% after treatment with 5-FU posing some problems for resection of liver metastasis and the risk of steatosis development correlates with body mass index [68]. Also, CASH is a common histological finding with different stages of damage, with metabolic features such as obesity and hyperglycemia being independent risk factors [69]. Of note, the presence of CASH has been reported to translate into higher 90-day postoperative mortality after hepatic resection of colorectal cancer metastases [67]. Valproate Valproate is a widely used antiepileptic drug [70] and associated with microvesicular steatosis, with hepatic steatosis being present in about 60% of patients treated with valproate [71]. Also, patients treated during long-term periods with valproate often develop features of MetS, such as increased BMI, dyslipidemia, and NAFLD [72]. Impairment in mitochondrial function appears to be an important effect of long-term valproate treatment, and it has been proposed as a risk factor for hepatotoxicity [60]. Acetaminophen Experimental studies in rodents suggest that acetaminopheninduced hepatotoxicity is adversely influenced by the presence of NAFLD [20]. Also, while some clinical studies reported that NAFLD could be a risk factor for acetaminopheninduced acute liver injury, others do not (reviewed in refs. [5•] and [73]). Michaut and colleagues have proposed that a balance between CYP2E1 (generally increased in obesity but with a high degree of variability) and other factors such as a higher rate of acetaminophen glucuronidation, reduced CYP3A4 activity, and increased volume of body distribution could influence the outcome of acetaminophen-induced hepatotoxicity in subjects with NAFLD [73].
Conclusions and Future Directions Given the lack of specific markers, DILI is a matter of concern and remains a diagnostic challenge in different clinical scenarios. The prevalence of MetS, its components, and its liver manifestation as NAFLD have increased in recent years, and probably will continue rising. In this scenario, the diagnosis, clinical course, and prognosis of DILI in the context of MetS and NAFLD may have some peculiarities that are still not well-characterized. Current evidence indicates that the prevalence of DILI is not higher in MetS and NAFLD than in other chronic liver diseases. Nevertheless, the phenotype of presentation and severity of DILI seems to be influenced by the
presence of NAFLD and MetS-related metabolic factors, which are of a more severe clinical presentation, higher mortality, and increased risk of chronic DILI. Polymedication of patients with MetS and NAFLD related to the existence of several comorbidities [74] may, to some extent, contribute to an increased risk of DILI in this patient population, but the magnitude of this effect is unknown. Also, causative drug agents of DILI appear to be similar in patients with MetS and in patients without this condition. Finally, causality assessment of a DILI episode could be particularly complex when metabolic syndrome and NAFLD are present. In conclusion, in spite of the increased susceptibility to liver damage and the significant changes in hepatic uptake, distribution, metabolism, and transport of drugs prescribed in NAFLD, many drugs appear to be safe and well tolerated in patients with this disease. Indeed, data on DILI occurring in the context of MetS and NAFLD is still scarce with no definitive evidence that a NAFLD background, with the exception of few drugs, critically influences features or severity of DILI. Prospective studies focused in this special patient population are warranted. Acknowledgements This article was partially supported by the AASLD Foundation (AASLD/LIFER Clinical and Translational Research Fellowship in Liver Diseases 2016 to J.P.A.). Support from the government of Chile through the Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT 1150327 to M.A.) and the Comisión Nacional de Investigación Científica y Tecnológica (grant CONICYT PIA/Basal PFB12, Basal Centre for Excellence in Science and Technology to M.A.) is also acknowledged. Compliance with Ethical Standards Conflict of Interest FERNANDO BESSONE is a Section Editor for Current Hepatology Reports. RAUL J. ANDRADE is a Section Editor for Current Hepatology Reports. JOSE IGNACIO VARGAS, JUAN PABLO ARAB, MARIA ISABEL LUCENA, and MARCO ARRESE declare no conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
Chalasani NP, Hayashi PH, Bonkovsky HL, Navarro VJ, Lee WM, Fontana RJ, et al. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014;109(7):950–66. quiz 67
Curr Hepatology Rep 2.• Chen M, Suzuki A, Borlak J, Andrade RJ, Lucena MI. Druginduced liver injury: Interactions between drug properties and host factors. J Hepatol. 2015;63(2):503–14. Excellent general review on drug-associated and host factors for DILI. 3. Fromenty B. Drug-induced liver injury in obesity. J Hepatol. 2013;58(4):824–6. 4. Pais R, Rusu E, Ratziu V. The impact of obesity and metabolic syndrome on chronic hepatitis B and drug-induced liver disease. Clin Liver Dis. 2014;18(1):165–78. 5.• Massart J, Begriche K, Moreau C, Fromenty B. Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity. J Clin Transl Res. 2017;3(Suppl 1):212–32. An updated and in-depth review on the role of NAFLD as a risk factor for DILI. 6. Arroyo-Johnson C, Mincey KD. Obesity Epidemiology Worldwide. Gastroenterol Clin North Am. 2016;45(4):571–9. 7. Grundy SM. Metabolic syndrome update. Trends Cardiovasc Med. 2016;26(4):364–73. 8. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—metaanalytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84. 9. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2017. 10. Targher G, Byrne CDA. Perspective on metabolic syndrome and nonalcoholic fatty liver disease. Metab Syndr Relat Disord. 2015;13(6):235–8. 11. Yang SQ, Lin HZ, Lane MD, Clemens M, Diehl AM. Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. Proc Nat Acad Sci U.S.A. 1997;94(6):2557–62. 12. Chu MJ, Hickey AJ, Phillips AR, Bartlett AS. The impact of hepatic steatosis on hepatic ischemia-reperfusion injury in experimental studies: a systematic review. Biomed Res Int. 2013;2013: 192029. 13. Arab JP, Arrese M, Trauner M. Recent insights into the pathogenesis of non-alcoholic fatty liver disease. Annual Review Pathology Mechanisms Disease. 2018 (in press). 14. Liu W, Baker SS, Baker RD, Zhu L. Antioxidant mechanisms in nonalcoholic fatty liver disease. Curr Drug Targets. 2015;16(12): 1301–14. 15. Begriche K, Massart J, Robin MA, Bonnet F, Fromenty B. Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease. Hepatology. 2013;58(4):1497–507. 16. Nair S, PC V, Arnold C, Diehl AM, Hepatic ATP. Reserve and efficiency of replenishing: comparison between obese and nonobese normal individuals. Am J Gastroenterol. 2003;98(2):466–70. 17. Cortez-Pinto H, Chatham J, Chacko VP, Arnold C, Rashid A, Diehl AM. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA. 1999;282(17):1659–64. 18. Thakkar N, Slizgi JR, Brouwer KLR. Effect of liver disease on hepatic transporter expression and function. J Pharm Sci. 2017;106(9):2282–94. 19. Merrell MD. Cherrington NJ. Drug metabolism alterations in nonalcoholic fatty liver disease. Drug Metab Rev. 2011;43(3):317–34. 20. Aubert J, Begriche K, Delannoy M, Morel I, Pajaud J, Ribault C, et al. Differences in early acetaminophen hepatotoxicity between obese ob/ob and db/db mice. J Pharmacol Exp Ther. 2012;342(3): 676–87. 21.• Dietrich CG, Rau M, Jahn D, Geier A. Changes in drug transport and metabolism and their clinical implications in non-alcoholic fatty liver disease. Expert Opinion on Drug Metabolism & Toxicology. 2017;13(6):625–40. An updated review on NAFLD-associated liver functions changes and its impact in the clinical setting.
22.
Bjornsson ES, Bergmann OM, Bjornsson HK, Kvaran RB, Olafsson S. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144(7):1419–25. 25 e1-3; quiz e19-20 23. Sgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet C, et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology. 2002;36(2):451–5. 24. Bessone F, Hernandez N, Lucena MI, Andrade RJ. Latin Dili Network L, Spanish Dili R. The Latin American DILI Registry experience: a successful ongoing collaborative strategic initiative. Int J Mol Sci. 2016;17(3):313. 25. Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, et al. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN Prospective Study. Gastroenterology. 2015;148(7):1340–52 e7. 26. Andrade RJ, Lucena MI, Fernandez MC, Pelaez G, Pachkoria K, Garcia-Ruiz E, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology. 2005;129(2):512–21. 27. Medina-Caliz I, Robles-Diaz M, Garcia-Munoz B, Stephens C, Ortega-Alonso A, Garcia-Cortes M, et al. Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury. J Hepatol. 2016;65(3):532–42. 28. Ruiz-salas A, Gonzalez Jimenez A, Stephens C, Medina-Caliz I, Hidalgo R, Robles-diaz M, et al. Influence of body mass index and metabolic risk factors on the phenotype and clinical expression of drug-induced liver injury (abstract). Ann Hepatol. 2014;13(5):601. 29. Garcia-Cortes M, Stephens C, Lucena MI, Fernandez-Castaner A, Andrade RJ. Causality assessment methods in drug induced liver injury: strengths and weaknesses. J Hepatol. 2011;55(3):683–91. 30. Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc. 2014;89(1):95–106. 31. Ortega-Alonso A, Stephens C, Lucena MI, Andrade RJ. Case characterization, clinical features and risk factors in drug-induced liver injury. Int J Mol Sci. 2016 17(5). 32.•• Kullak-Ublick GA, Andrade RJ, Merz M, End P, Benesic A, Gerbes AL, et al. Drug-induced liver injury: recent advances in diagnosis and risk assessment. Gut. 2017;66(6):1154–64. An updated and in-depth review on current concepts on DILI. 33. Maximos M, Bril F, Portillo Sanchez P, Lomonaco R, Orsak B, Biernacki D, et al. The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease. Hepatology. 2015;61(1):153–60. 34. Lee TH, Kim WR, Poterucha JJ. Evaluation of elevated liver enzymes. Clin Liver Dis. 2012;16(2):183–98. 35. Dakhoul L. N. C. Causality assessment for suspected drug-induced liver injury in patients with underlying chronic liver disease. Clinical Liver Disease. 2017;9(3):63–5. 36. Farrell GC. Drugs and steatohepatitis. Semin Liver Dis. 2002;22(2): 185–94. 37. Tujios S, Fontana RJ. Mechanisms of drug-induced liver injury: from bedside to bench. Nature reviews. Gastroenterology & hepatology. 2011;8(4):202–11. 38. Connolly SJ. Evidence-based analysis of amiodarone efficacy and safety. Circulation. 1999;100(19):2025–34. 39. Kum LC, Chan WW, Hui HH, Wong GW, Ho SS, Sanderson JE, et al. Prevalence of amiodarone-related hepatotoxicity in 720 Chinese patients with or without baseline liver dysfunction. Clin Cardiol. 2006;29(7):295–9. 40. Pollak PT, Shafer SL. Use of population modeling to define rational monitoring of amiodarone hepatic effects. Clin Pharmacol Ther. 2004;75(4):342–51. 41. Mattar W, Juliar B, Gradus-Pizlo I, Kwo PY. Amiodarone hepatotoxicity in the context of the metabolic syndrome and right-sided heart failure. J Gastrointest Liver Dis JGLD. 2009;18(4):419–23.
Curr Hepatology Rep 42.
43.
44.•
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55. 56.
57.
Bjornsson E, Jacobsen EI, Kalaitzakis E. Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing. J Hepatol. 2012;56(2):374–80. Russo MW, Hoofnagle JH, Gu J, Fontana RJ, Barnhart H, Kleiner DE, et al. Spectrum of statin hepatotoxicity: experience of the druginduced liver injury network. Hepatology. 2014;60(2):679–86. Bril F, Portillo Sanchez P, Lomonaco R, Orsak B, Hecht J, Tio F, et al. Liver safety of statins in prediabetes or T2DM and nonalcoholic steatohepatitis: post hoc analysis of a randomized trial. J Clin Endocrinol Metab. 2017;102(8):2950–61. A prospective study on safety of statins in biopsy-proven NASH. Del Ben M, Baratta F, Polimeni L, Pastori D, Loffredo L, Averna M, et al. Under-prescription of statins in patients with non-alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis NMCD. 2017;27(2): 161–7. Athyros VG, Boutari C, Stavropoulos K, Anagnostis P, Imprialos KP, Doumas M, et al. Statins: an under-appreciated asset for the prevention and the treatment of NAFLD or NASH and the related cardiovascular risk. Curr Vasc Pharmacol 2017 Vargas JI, Arrese M, Shah VH, Arab JP. Use of statins in patients with chronic liver disease and cirrhosis: current views and prospects. Current Gastroenterol Rep. 2017;19(9):43. Dongiovanni P, Petta S, Mannisto V, Mancina RM, Pipitone R, Karja V, et al. Statin use and non-alcoholic steatohepatitis in at risk individuals. J Hepatol. 2015;63(3):705–12. Stika CS. Methotrexate: the pharmacology behind medical treatment for ectopic pregnancy. Clin Obstet Gynecol. 2012;55(2): 433–9. Candia R, Ruiz A, Torres-Robles R, Chavez-Tapia N, MendezSanchez N, Arrese M. Risk of non-alcoholic fatty liver disease in patients with psoriasis: a systematic review and meta-analysis. J Eur Acad Dermatol Venereol JEADV. 2015;29(4):656–62. Bath RK, Brar NK, Forouhar FA, Wu GYA. Review of methotrexate-associated hepatotoxicity. J Dig Dis. 2014;15(10): 517–24. Rosenberg P, Urwitz H, Johannesson A, Ros AM, Lindholm J, Kinnman N, et al. Psoriasis patients with diabetes type 2 are at high risk of developing liver fibrosis during methotrexate treatment. J Hepatol. 2007;46(6):1111–8. Berends MA, Snoek J, de Jong EM, van de Kerkhof PC, van Oijen MG, van Krieken JH, et al. Liver injury in long-term methotrexate treatment in psoriasis is relatively infrequent. Aliment Pharmacol Ther. 2006;24(5):805–11. Howell SJ, Johnston SR, Howell A. The use of selective estrogen receptor modulators and selective estrogen receptor downregulators in breast cancer. Best Pract Res Clin Endocrinol Metab. 2004;18(1):47–66. Pratt DS, Knox TA, Erban J. Tamoxifen-induced steatohepatitis. Ann Intern Med. 1995;123(3):236. Nishino M, Hayakawa K, Nakamura Y, Morimoto T, Mukaihara S. Effects of tamoxifen on hepatic fat content and the development of hepatic steatosis in patients with breast cancer: high frequency of involvement and rapid reversal after completion of tamoxifen therapy. AJR Am J Roentgenol. 2003;180(1):129–34. Bruno S, Maisonneuve P, Castellana P, Rotmensz N, Rossi S, Maggioni M, et al. Incidence and risk factors for nonalcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial. BMJ. 2005;330(7497):932.
58.
Oien KA, Moffat D, Curry GW, Dickson J, Habeshaw T, Mills PR, et al. Cirrhosis with steatohepatitis after adjuvant tamoxifen. Lancet. 1999;353(9146):36–7. 59. Cole LK, Jacobs RL, Vance DE. Tamoxifen induces triacylglycerol accumulation in the mouse liver by activation of fatty acid synthesis. Hepatology. 2010;52(4):1258–65. 60. Amacher DE, Chalasani N. Drug-induced hepatic steatosis. Semin Liver Dis. 2014;34(2):205–14. 61. Larosche I, Letteron P, Fromenty B, Vadrot N, Abbey-Toby A, Feldmann G, et al. Tamoxifen inhibits topoisomerases, depletes mitochondrial DNA, and triggers steatosis in mouse liver. J Pharmacol Exp Ther. 2007;321(2):526–35. 62. Birzniece V, Barrett PHR, Ho KKY. Tamoxifen reduces hepatic VLDL production and GH secretion in women: a possible mechanism for steatosis development. Eur J Endocrinol. 2017;177(2):137–43. 63. Kneeman JM, Misdraji J, Corey KE. Secondary causes of nonalcoholic fatty liver disease. Therapeut Adv Gastroenterol. 2012;5(3): 199–207. 64. Yan M, Wang J, Xuan Q, Dong T, He J, Zhang Q. The relationship between tamoxifen-associated nonalcoholic fatty liver disease and the prognosis of patients with early-stage breast cancer. Clinical Breast Cancer. 2017;17(3):195–203. 65. Verna EC. Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in patients with HIV. Lancet. Gastroenterol Hepatol. 2017;2(3):211–23. 66. Rabinowich L, Shibolet O. Drug induced steatohepatitis: an uncommon culprit of a common disease. Biomed Res Int. 2015;2015: 168905. 67. McWhirter D, Kitteringham N, Jones RP, Malik H, Park K, Palmer D. Chemotherapy induced hepatotoxicity in metastatic colorectal cancer: a review of mechanisms and outcomes. Crit Rev Oncol Hematol. 2013;88(2):404–15. 68. Makowiec F, Mohrle S, Neeff H, Drognitz O, Illerhaus G, Opitz OG, et al. Chemotherapy, liver injury, and postoperative complications in colorectal liver metastases. J Gastrointest Surg Off J Soc Surg Aliment Tract. 2011;15(1):153–64. 69. Brouquet A, Benoist S, Julie C, Penna C, Beauchet A, Rougier P, et al. Risk factors for chemotherapy-associated liver injuries: a multivariate analysis of a group of 146 patients with colorectal metastases. Surgery. 2009;145(4):362–71. 70. Taing KD, O'Brien TJ, Williams DA, French CR. Anti-epileptic drug combination efficacy in an in vitro seizure model—phenytoin and valproate, lamotrigine and valproate. PloS one. 2017;12(1): e0169974. 71. Luef GJ, Waldmann M, Sturm W, Naser A, Trinka E, Unterberger I, et al. Valproate therapy and nonalcoholic fatty liver disease. Ann Neurol. 2004;55(5):729–32. 72. Luef G, Rauchenzauner M, Waldmann M, Sturm W, Sandhofer A, Seppi K, et al. Non-alcoholic fatty liver disease (NAFLD), insulin resistance and lipid profile in antiepileptic drug treatment. Epilepsy Res. 2009;86(1):42–7. 73. Michaut A, Moreau C, Robin MA, Fromenty B. Acetaminopheninduced liver injury in obesity and nonalcoholic fatty liver disease. Liver Int. 2014;34(7):e171–9. 74. Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017;66(6):1138–53.
